Pain-related disorders cause an incalculable toll in human suffering and present a significant economic problem. The development of new treatments for these disorders is hindered by a lack of information about the basic neural mechanisms that process pain-related information. To date, investigations of the dynamic activation of mechanisms that facilitate pain have provided substantial insights into the neurophysiology and neuropharmacology of chronic pain. However, understanding of the dynamic response properties of inhibitory mechanisms has remained limited, despite the fact that disruption of inhibition may also contribute substantially to chronic pain. A recently identified analgesic phenomenon, offset analgesia, provides a powerful tool for the study of dynamic activation of inhibitory mechanisms. A series of psychophysical studies in humans subjects will systematically delineate the neurophysiological and neuropharmacological mechanisms that initiate and maintain offset analgesia during acute pain states, and determine the contribution of disrupted offset analgesia to pathophysiological pain states. Together, these studies will significantly enhance our knowledge of basic neural mechanisms underlying pain and will provide a foundation for the development of novel treatments for pain.